The present invention generally relates to devices and methods for characterizing sample materials. In an exemplary embodiment, the invention provides a time-of-flight (TOF) mass spectrometer that allows overlapping packets of ions to be mathematically resolved into a mass spectrum. A variety of related methods, devices, and systems are also provided.
Mass spectrometers are widely used in research for characterization and identification of biological compositions and biological substances. Mass spectrometers often analyze variations or dispersions of ion movement under electric or magnetic fields, and are particularly useful for determining properties such as molecular mass of ions and sequence information of interest.
A wide variety of ionization sources have been developed, with many of these of being intended for ionization of biological compounds. Ion sources often make use of vacuum chambers to ionize the compounds of interest at very low pressures using electrical field ionization, thermal ionization, photo-ionization, and other techniques. More recently, characterization of complex biological compounds has been advanced by the introduction of ionization sources operating at elevated pressures, including atmospheric pressure. Such pressure environments may provide efficient and “soft” ionization of large complex biological substances, e.g., proteins. Electrospray ionization (ESI) is among the most popular atmospheric pressure ionization techniques, although matrix assisted laser desorption ionization (MALDI) and related techniques have also found beneficial applications in atmospheric and intermediate pressure ranges.
A variety of analyzer technologies have been developed, including analyzers which measure the travel time or “time-of-flight” of ions along a flight path, i.e., TOF instruments. In general, as biological research has expanded in the field of proteomics it has become desirable to develop analyzers which would contribute to a more complete understanding of protein functions in a cellular context. Toward that end, it would be advantageous to provide high sensitivity, a wide dynamic range, and an improved duty cycle so as to facilitate the study of cellular pathways, as many important protein classes are present at quite low concentrations.
A wide variety of mass spectrometer analyzers may be coupled to an ESI (or other) ion source, including Fourier transform ion cyclotron resonance (FTICR), quadrupole ion storage trap, and TOF mass spectrometers. FTIR mass spectrometers may provide baseline isotopic mass resolutions of proteins with molecular masses up to 10 kDa, and may detect sub attomole (less than 600,000 molecules) quantities of proteins at a very high duty cycle. However, FTICR mass spectrometers have limitations on the speed of analysis. Shortening the detection time (and therefore truncating the ion signal transients) would deteriorate mass resolution, making these analyzers better suited for extended separation times.
Alternative known mass analyzers also have drawbacks in either speed or performance. For example, quadrupole ion trap mass spectrometers may provide a higher speed analysis than FTICR, but may be limited to a lower resolution and dynamic range. While improvements in resolution and sensitivity can be provided, these improvements generally results in decreases in the duty cycle and the speed of analysis. TOF mass spectrometers with orthogonal acceleration (OA-TOF) may provide both high-speed analysis and relatively high-mass resolution, along with high sensitivity. However, these instruments generally send packets of ions toward a detector in a “release and wait” approach, yielding a limited duty cycle. Hence, each of these known analyzer technologies has significant limitations with respect to rapid quantitative analysis of protein extracts.
A new time-of-flight mass spectrometer has recently been developed in an attempt to address some of the limitations of prior analyzer structures. The Hadamard transform TOF mass spectrometer makes use of a Bradbury-Nielsen Gate disposed along the ion path so as to encode a continuous ion beam with an on-axis “on” and “off” pseudo-random binary sequence, followed by mathematical recovery of the acquired signal.
In general, mass spectrometers have evolved over the years to highly accurate (albeit complex) research tools. Further improvements in existing mass spectrometry instruments for use by researchers will continue to be beneficial. Moreover, it may be possible to transfer at least some of these improvements more directly into improved healthcare. This technology transfer may involve a fundamental shift; medical diagnosis may in the future make use of mass spectrometry, which has basically been a research tool. For example, it may be possible to use improved mass spectrometers to identify the presence of small quantities of a particular protein or set of proteins (or other marker substances) which can reliably detect or predict a specific biological state in a patient (such as cancer or other disease states) earlier and/or more reliably than conventional approaches. To enable this very different use, the reliability, ease of use, and reproducibility of biological sample analysis by existing research mass spectrometers should be dramatically improved. Additionally, it would be highly beneficial to provide a combination of good mass resolution, high sensitivity, and accuracy with a faster analysis time and throughput so as to allow a significant number of samples (for example, from a large number of patients) to be analyzed in a given amount of time by a single system.
For the reasons given above, it would be desirable to provide improved devices, methods, and systems, for characterizing biological and other samples. It would be particularly beneficial to provide improved mass spectrometers and mass spectrometry analysis methods, especially if these improvements provided a combination of good mass resolution, sensitivity and accuracy, together with a short analysis time so as to facilitate a high throughput of samples.